As of 2006, an estimated 40 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60 % of infected individuals, even in the antiretroviral era. Although, there was an initial drop in the incidence of cognitive impairment and other neurological manifestations with the introduction of therapies, the prevalence of neurological complications due to HIV CNS infection has actually increased as infected individuals are living longer. However, the cellular basis and mechanisms by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood nor is how to identify which HIV-infected individuals will become cognitively impaired. A key axis in the immune system, the interactions between CD40-CD40 ligand (CD40L) is essential for immune cell activation. A soluble isoform of CD40L (sCD40L), cleaved from the cell surface, can be detected minimally in sera of healthy individuals, but its role is unknown. We have new data that sera from HIV-infected individuals with cognitive impairment but not from those with no impairment have high circulating levels of sCD40L, suggesting a role for this protein in HIV dementia. We hypothesize that serologic sCD40L can serve as a predictive marker for cognitive impairment in HIV infected individuals. To address this hypothesis we will expand our Preliminary Studies demonstrating the correlation between CNS dysfunction and sCD40L levels in the sera of HIV-infected people using two well characterized cohorts of individuals, CHARTER and The Manhattan Brain Bank. These individuals have had extensive neuropsychological evaluations and many have been evaluated by MRI/MRS. We also will determine when during the course of CNS cognitive decline sCD40L levels are increased within the brain using brain tissue sections from individuals with different degrees of cognitive compromise. These data will identify a potential serologic predictor of cognitive impairment and dementia in HIV-infected individuals and thus should identify a potential therapeutic target to limit the devastating consequences of NeuroAIDS. PUBLIC HEALTH RELEVANCE: HIV infection and recently HIV Neurocognitive impairment are a major emerging global health problem. Its prevalence is increasing as people with AIDS are living longer due to success of antiretroviral therapies. Currently, there are no available serologic predictors of HIV induced cognitive impairment and, in general, cognitive deficits are detected late in the course of the disease. Our preliminary data indicate that serologic levels of soluble CD40 ligand (sCD40L) may be an early predictor of cognitive impairment and dementia, and therefore suggest the CD40-CD40L axis as a target for therapies to reduce HIV CNS impairment.